Chiral glycerol derivatives

ABSTRACT

Enantiomerically pure glycerol derivatives, e.g. S-1,2-O-isopropylidene, S-1,2-O-benzylidene, and R-1,2-O-dibenzyl glycerol, have been prepared from 1,2R-O-protected erythritols in high yields. The latter compounds are easily obtained from erythorbic acid and are useful building blocks in the synthesis of a host of optically active compounds having biological activity.

This application is a continuation of application Ser. No. 07/852,885file Mar. 17, 1992, now abandoned, which is a continuation ofapplication Ser. No. 07/505,246 filed Apr. 5, 1990, now abandoned, whichis a divisional of application Ser. No. 07/025,624 filed Mar. 13, 1987,now U.S. Pat. No. 4,931,575.

DESCRIPTION OF THE INVENTION

1. Technical Field of the Invention

This invention relates to a process and compounds useful for thepreparation of R-- and S-- glycerol derivatives, common building blocksfor a number of chiral natural and synthetic products, from a singleintermediate in high yields. Both R-- and S-- isomers can be prepared byselective cleavage of either the C1-C2 or C3-C4 bonds in a properlyprotected, and thus chiral, erythritol derivative. In anotherembodiment, this invention relates to a process and compounds useful forobtaining such building blocks in enantiomerically pure form.

2. Background Art

Chirality, or "handedness", is a term which was first applied by LordKelvin to any geometric shape having an image in a plane mirror whichcannot be brought to coincide with itself, as with our left and righthands. Atoms to which different ligands are attached at each of three orfour valances (e.g., carbon, nitrogen, phosphorus, etc.) form a chiralcenter, which is a necessary and sufficient condition for the existenceof optically active mirror-image isomers known as enantiomers.

Enantiomers show different properties, both physical and chemical, onlyin a chiral medium, e.g. irradiation with plane or circularly polarizedlight, reaction with an optically active reagent, solubility in anoptically active solvent, or adsorption onto an optically activesurface.

The maximum number of stereoisomers that can exist is 2n where n is thenumber of chiral centers in a molecule. Compounds containing a pluralityof chiral centers can also exist as diastereomers, which arestereoisomers that are not mirror images of each other. Diastereomershave similar (but not identical) chemical properties and differentphysical properties which facilitate separation into their racemicmixtures which can then be resolved by the use of optically activereagents.

Characterization of a particular isomer's configuration is determined byapplying a well-known set of sequence rules to assign priorities to theligands which are attached to the chiral center, after which themolecule is visualized With the lowest priority ligand directed awayfrom the viewer. If proceeding from the highest priority ligand to thoseof the second and third priority is a clockwise direction, theconfiguration is specified R; if counterclockwise, S. Because thisconfiguration has no relationship to the direction of optical rotation,a complete name for an optically active compound reveals bothconfiguration and direction of rotation, e.g. (S)-(+)-sec-butylchloride.

Where compounds contain more than one chiral center, the configurationabout each center is specified together with the nomenclature number ofthe chiral carbon atom, e.g. (2S,3S)- and (2R,3R)- compounds areenantiomers having opposite configurations for each chiral center,whereas (2S,3S)- and (2S,3R)- compounds would be diastereomers with thesame configuration about one chiral center and the oppositeconfiguration about the other.

Stereoisomers are ubiquitous building blocks in nature. For example,(+)-glucose contains five chiral centers which give rise to 32stereoisomers. Naturally occurring glucose in the alpha-form is themonomeric unit of starch, from which our food ultimately comes, whereasbeta-D-glucose is the monomeric unit of cellulose, the framework ofplants that synthesize starch.

Glycerol is a simple trihydric alcohol having thousands of uses as anindustrial chemical and as a starting material for the preparation ofmany pharmaceuticals by reactions which involve substitutions Of one ormore primary hydroxyl groups in the glycerol molecule. Such asubstitution of glycerol (which has a "pro-chiral" center at C2 which iscapable of becoming a chiral carbon atom) is a desired starting materialfor the synthesis of optically active glycerol derivatives. Because thesynthesis of chiral compounds from achiral reactants always yields theoptically inactive (RS) racemic mixture, the ability to generate a pureenantiomer starting material would effectively multiply the final yieldof a desired isomer in products such as those prepared by a reactionthat does not involve the breaking of a bond to a chiral center.

One example of a pharmaceutical glycerol derivative is the chiralsynthon (chiron) 2,3-O-isopropylidene-L-glycerol or(R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol described in K. H. X. Maiand G. Patil U.S. Pat. No. 4,575,558 as an important intermediate forpreparing optically active beta-adrenergic agonists and antagonists andas a chiral building block in a number of natural products. Theoptically active glycerol derivatives used for the preparation of thesemolecules are derived from D- and L-serine. The presence of thesubstituted glycerol backbone in such compounds lends itself tosynthesis using the methods of the present invention.

J. J. Baldwin and D. E. McClure U.S. Pat. No. 4,588,824 describe aprocess for preparing the (S)-enantiomer of Mai. et al.,(S)-glycerol-1,2-acetonide or(S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol by treating1,2:5,6-di-O-isopropylidene-D-mannitol with lead tetraacetate in anaprotic solvent, reducing the optically active glyceraldehyde reactionproduct with an alkali metal borohydride and treating the reactionmixture with an ammonia halide to form the (S)-glycerol derivative. Theproduct is a useful intermediate for the preparation of either the (S)--or (R)-- enantiomer of epihalohydrins from the same starting materialwithout requiring costly and inefficient racemic resolution procedures.

R. M. Carman and J. J. Kibby describe the preparation of chiralbenzylidene derivatives of glycerol in Aust. J. Chem 29:1761-67 (1976)by a method admittedly cumbersome, tedious, and difficult to duplicate.

J. Jarczak et al. have recently reviewed the role of (R)-- and (S)--2,3-O-isopropylideneglyceraldehyde in stereoselective organic synthesisin Tetrahedron Report No. 195, Tetrahedron 142 (2): 447-487 (1986).Starting from the three-carbon glycerol backbone, techniques aredescribed for building to compounds having 20 and more carbon atoms,e.g. lecithins, glycerol-3-phosphates, macrobicyclic polyethers andriboses (page 455); natural products including brefeldin (a sexpheromone), leukotrienes such as LTA4, and prostaglandins (see pages479-485). The glyceraldehydes undergo many of the same chemicalreactions as their corresponding glycerols but are less storage stabledue to their tendency to polymerize.

Although the chemistry of L-ascorbic acid has been thoroughly studied,that of its C-5 isomer, D-isoascorbic acid, remains relativelyunexplored. The synthetic utility of D-isoascorbic acid is not limitedto the preparation of R-- and S-- glycerol derivatives. It, along withL-ascorbic acid, serves as an attractive precursor for the preparationof new selectively protected chiral erythritols and threitols, which, intheir own right, are attractive building blocks in organic synthesis.

Synthetic approaches to 2-deoxy-2-amino-D-threose have been described ina 1982 thesis by David C. J. Wu (Department of Medicinal Chemistry,University of Rhode Island) as a potential synthon for adenosinedeaminase inhibitors. However, there is no suggestion that the3,4-O-isopropylidine-D-erythritol intermediate in that process would beuseful as a source of enantiomerically pure R-- or S-- diastereomers inaccordance with the present invention.

DISCLOSURE OF THE INVENTION

Accordingly, it is a general object of the present invention to providea method for the synthesis of optically active glycerol derivativeswherein either the (R)-- or (S)-- enantiomer can be prepared from thesame starting material.

Another object of the present invention is to provide a method for theutilization of 1,2-O-protected (and thus chiral) erythritol derivativesas chiral synthons or chirons.

An additional object of this invention is to provide a method andcompounds useful therein whereby these same chiral erythritolderivatives can be used as a building block to which one carbonfragments in the proper oxidation state can be added to provideenantiomerically pure compounds such as 3,5-di-O-protected2-deoxypentofuranoses and their glycosides.

A further object of the present invention is to provide a process forthe preparation of optically active chiral phosphorylated acyclicnucleosides having chemotherapeutic activity, especially cytotoxic orantiviral activity, e.g. derivatives of acyclovir.

A more particular object of the present invention is to provide a methodfor the preparation of optically active chiral platelet-activatingfactor (PAF) and other fatty acid ethers and esters.

Upon study of the specification and appended claims, further objects,features and advantages of the present invention will become more fullyapparent to those skilled in the art to which this invention pertains.

BEST MODE FOR CARRYING OUT THE INVENTION

Briefly, the above and other objects, features and advantages of thepresent invention are attained in one aspect thereof by providing aprocess for preparing a R-2,3-O-protected glyceraldehyde, whichcomprises:

a) selecting a corresponding 2R,3S-1,2-O-protected butane1,2,3,4-tetrol;

b) reacting said tetrol under conditions which preserve the cyclicacetal 1,2-O-protecting group while cleaving the C3-C4 bond to formenantiomerically pure R-2,3-O-protected glyceraldehyde; and

c) recovering said enantiomerically pure R-2,3-O-protectedglyceraldehyde.

In a second aspect of this invention, enantiomerically pure3,5-di-O-protected 2-deoxypentofuranoses and their glycosides selectedfrom the group consisting of 2-deoxy-L-xylose, 2-deoxy-L-ribose,2-deoxy-D-xylose and 2-deoxy-D-ribose, are prepared by a process whichcomprises:

a) selecting a corresponding 4,5-O-arylidine-3-O-protected3,4,5-trihydroxy pentanonitrile of Formula 7, 8, 9 or 10 as shown inFIG. 3 wherein Ar is carbocyclic aromatic and R is an aliphatic,cycloaliphatic, arylkl (e.g. benzyl), silyl or the like O-protectinggroup as defined herein which is more stable to cleavage than CN; and

b) reducing the 4,5-O-arylidine-3-O-protected 3,4,5-trihydroxypentanonitrile to form a corresponding D- or L- sugar of Formula 11, 12,13 or 14, respectively, as shown in FIG. 3.

In a third aspect of this invention which can be schematically seen inFIG. 2, there is provided a method for the preparation of opticallyactive chiral phosphorylated acyclic nucleosides or platelet activatingfactor (PAF) analogues.

The potential utility of this work is evident in natural products anddrug synthesis. For example, dihydroxy-propoxymethyl guanine (DHPG) is apotent antiviral drug which has a glycerol backbone that must bephosphorylated at only one site by a viral enzyme before exerting itsanti-herpetic action. Therefore DHPG becomes ineffective if the targetvirus lacks a phosphorylating enzyme. Therefore a logical solution tothis problem could be reached by chemical, rather than enzymaticphosphorylation of DHPG. This, however, unlike enzymaticphosphorylation, produces a racemic (50:50) mixture of drug isomerswhere only one isomer has biological activity. Being able to produce theright (active) isomer is therefore an attractive process, bothscientifically and economically; such a process is provided in a fourthaspect of this invention.

In a fifth aspect, the present invention provides a method for preparingisomerically pure (R)-- or (S)-enantiomers of platelet-activating factor(PAF) and related compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

This invention Will be more fully appreciated by those skilled in theart to which it pertains by reference to the accompanying Drawings,wherein:

FIG. 1 is a schematic illustration of the reaction sequences andintermediates formed according to a process of the invention forpreparing enantiomerically pure isomers of either the (R)-- or (S)--configuration from the same starting material;

FIG. 2 schematically illustrates the reaction sequences andintermediates formed in a process of the present invention for thepreparation of optically active (a) chiral phosphorylated acyclicnucleosides having chemotherapeutic activity, especially cytotoxic orantiviral activity (left side), or alternatively (b) chiral PAF andother fatty acid ethers and esters (right side);

FIG. 3 schematically illustrates the reaction sequences andintermediates formed according to a process of this invention forpreparing enantiomerically pure 3,5-di-O-protected 2-deoxypentofuranosesand their glycosides; and

FIG. 4 schematically illustrates the reaction sequences andintermediates formed in a process of the present invention for thepreparation of analogs of acyclovir.

DETAILED DESCRIPTION

Referring to the Formulae of FIGS. 1 through 4, R, R' and R" are eachaliphatic or cycloaliphatic. Aliphatic or cycloaliphatic is preferablyof up to six carbon atoms, e.g., alkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl. Suitable alkyl groups include but are not limited tomethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl andtert.-butyl. Suitable alkenyl groups include but are not limited tovinyl, 2,2 -dimethylvinyl, allyl, dimethylallyl, 1-propenyl, 1-butenyl,2-butenyl, 3-meththyl-2-butenyl, 1-pentenyl and 2-pentenyl. Suitablealkynyl groups include but are not limited to propynyl, butynyl andpentynyl. Suitable cycloalkyl groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl optionallysubstituted, e.g., by alkyl or alkenyl of up to four carbon atoms toform cycloalkylalkyl or cycloalkylalkenyl, e.g., cyclopropylmethyl.Suitable cycloalkenyl groups include but are not limited tocyclobutenyl, cyclopentenyl and cyclohexenyl optionally substituted,e.g., by alkyl or alkenyl of up to four carbon atoms to formcycloalkenylalkyl orcycloalkenylalkenyl, e.g., cyclobutenylethyl.

In FIGS. 3 and 4, Ar is carbocyclic aromatic. Carbocyclic aromatic canbe aryl or alkaryl. Carbocyclic aryl is preferably phenyl, naphthyl orsubstituted phenyl; carbocyclic alkaryl is preferably alkylphenyl orsubstituted alkylphenyl, e.g., tolyl. Suitable substituents of thecarbocyclic aromatic group are 1-3 lower alkyl groups, e.g., methyl; 1-3lower alkoxy groups, e.g., methoxy or ethoxy; and 1-3 halogen atoms,e.g., fluorine (including trifluoromethyl), chlorine or bromine.Suitable substituted carbocyclic aromatic groups include but are notlimited to o-, m- or p- tolyl; o-, m- or p- methoxyphenyl; o-, m- orp-fluorophenyl; o-, m- or p-chlorophenyl; and alpha- or beta- naphthyl.

In a first aspect of this invention, enantiomerically pure R-isomers ofglycerol are prepared by selective cleavage of the C1-C2 bonds of chiralerythritol derivatives which are1,2,3,4-tetra-O-protected-butane-1,2,3,4-tetrols of Formula 8 in FIG. 1in which the C1-C2 protecting groups are susceptible to cleavage underconditions which do not cleave the C3-C4 protecting groups.

Suitable hydroxyl masking groups are well known in the art and includebut are not limited to an acyl group (e.g., an alkanoyl group of 2-5carbon atoms such as acetyl, propionyl and butyryl, or an aroyl groupsuch as benzoyl), an arylmethyl group (e.g., benzyl), and alkylsulfonylgroup (e.g., an alkylsulfonyl of 1-4 carbon atoms such as methylsulfonylor ethylsulfonyl), an aralkylsulfonyl group (e.g., benzylsulfonyl) or anarylsulfonyl group (e.g., phenylsulfonyl or p-toluylsulfonyl).

It is necessary that the chemical reactivity of the protecting groups(if any) at positions 1 and 2 be different from those at positions 3 and4. Such arrangements are known in the art and have been described, forexample, by Dr. Theodora W. Greene in Protective Groups in OrganicSynthesis, John Wiley and Son, New York (1981). For example, silylethers, alkoxy alkyl ethers, aryloxy alkyl ethers, acetals, ketals andTHP cyclic ethers (cleaved by mild acidic hydrolysis) or esters (cleavedby basic hydrolysis) can be prepared to protect isolated hydroxylgroups; 1,2-diols can be protected as cyclic ethers (e.g., alkylidene,arylidene, etc., cleaved by acidic hydrolysis) or as cyclic esters,e.g., cyclic carbonates and cyclic boronates (cleaved by basichydrolysis). Benzyl or substituted benzyl masking groups can be usedwhen cleavage by hydrogenolysis is desired.

In a second aspect of this invention, enantiomerically pure S-isomers ofglycerol are prepared by selective cleavage of the C3-C4 bonds of chiralerythritol derivatives of Formula 5 in FIG. 1 which are1,2-di-O-protected-butane-1,2,3,4-tetrols.

The second aspect of this invention involves a reductive opening of anunsymmetrical 2-aryl 1,3-dioxolane (arylidene) ring, e.g., using sodiumcyanoborohydride. The application of this well described literatureprocedure to 1,2-O-arylidene glycerol derivatives allows the preparationof a primary benzyl ether and a free secondary hydroxyl group atpositions one and two of glycerol. Since chirality at C-2 is determinedby atomic number priorities of its substituents, it can be easily seenthat manipulation of these priorities, and thus chirality at C-2, can beeasily accomplished by selective deblocking at C-1 or C-3.

When the hydroxyl-masking group is of the acyl type such as alkanylremoval can be accomplished by alkaline hydrolysis using aqueous sodiumhydroxide, ammonia in methanol or sodium methylate in methanol. When thehydroxyl-masking group is isopropylidene, cyclohexylidene, benzylidene,tetrahydropyranyl or methoxycyclohexyl, removal can be accomplished bymild hydrolysis using diluted hydrochloric acid or aqueous acetic acid.When the hydroxyl-masking group is benzyl, p-toluyl or the like, removalcan be achieved by catalytic hydrogenolysis in the presence of palladiumon carbon.

As illustrated in FIG. 1, starting with D-isoascorbic acid (1a)1,2R-O-isopropylidene erythritol (5a) has been prepared from5,6-O-isopropylidene D-isoascorbic acid (2a); 1H nmr (acetone-d6):delta1.3 and 1.37 (two 3H, s), 3.6-3.9 (2H, 4.37 (1H, m), 4.75 (1H, d, J=3Hz), 8.4 (2H, br s).

Both 5,6-O-isopropylidene and 5,6-O-benzylidene D-isoascorbic acid (2aand 2a) were oxidatively cleaved without purification. Potassium3,4-O-isopropylidene-D-erythronate (3a) was separated from inorganicby-products by extraction with anhydrous ethanol. Treatment of 3a withiodomethane in refluxing acetonitrile gave methyl ester 4a [alpha] _(D)-23.87 (C 4.84, EtOH); 1H nmr (CDCl₃): delta 1.33 and 1.40 (two 3H, s),3.6 (1H, s), 3.73 (3H, s) 3.95 (2H, d, J=6 Hz), 4.18 (2H, m) in 76%yield from D-isoascorbic acid. Compound 4b was obtained similarly as amixture of diastereomers showing benzylidene protons at delta 5.7 and6.0 ppm.

Lithium aluminum hydride reduction of 4a in ether gave diol 5a as an oilin 82% yield; [alpha] _(D) +5.83 (C 8.28, EtOH); 1H nmr (DMSO-d6); delta1.25 and 1.30 (two 3H, s), 3.21-4.0 (6H, m), 4.61-4.93 (2H, m). Likewisediol 5b was obtained as a diastereomeric mixture. S-1,2-O-isopropylideneglycerol (7a) was obtained from 5a by cleavage with sodium periodate andreduction of the resulting R-aldehyde (6) with sodium borohydride. TheS-1,2-O-benzylidene isomer (7b) was obtained in an identical manner from5b; 1H nmr (CDCl₃) : delta 2.4 (1H, br s), 3.5-4.4 (5H, m), 5.73, 5.8(two 1/2H, s, diastereomeric benzylidene protons), 7.2-7.5 (5H, m).

R-1,2-Di-O-benzylglycerol 11 was then obtained from diol 5a. Benzylationof 5a (NaH, DMF) furnished the dibenzyl derivative (8); [alpha] _(D)+16.77 (C 2.96, EtOH); 1H nmr (CDCl₃): delta 1.27 and 1.32 (two 3H, s),3.52 (3H, m), 3.88 (3H m) 4.37 (2H s) 4.52 (2H, ABq, J=14 Hz) 7.16 (10H,s). Cleavage of the ketal (90% aqueous ethanol, IR-120 Plus) affordeddiol 9: [alpha] _(D) +4.21 (C 1.46, EtOH). Successive treatment of 9with sodium periodate and sodium borohydride furnished glycerol 11;[alpha] _(D) +1.31 (C 3.21, EtOH), lit. 16+3.8 (neat); 1H nmr (CDCl₃):delta 2.2 (1H, br s), 3.43-3.83 (5H, m), 4.46 (2H, s), 4.46-4.73 (2H,ABq, J=12 Hz), 7.2-7.36 (10H, m).

In a third aspect of this invention, it has been found that these samechiral erythritol derivatives can be used as a building block to whichone carbon fragment in the proper oxidation state can be added toprovide enantiomerically pure compounds-such as3,5-di-O-protected-2-deoxypentofuranoses and their glycosides.

Briefly, this can be achieved according to the present invention by areaction sequence using a 1,2-O-benzylidine-butane 1,2,3,4-tetrolstarting material in which the unprotected 3- and 4-hydroxyl groups areconverted to an epoxide, e.g. via the Mitsunobu reaction described in areview appearing in Synthesis 1:1-28 (1981). This reaction involvesreaction with diethyl azodicarboxylate and triphenylphosphine to form,for example, a 2S,3R-1,2-anhydro-3,4-arylidene-butane-1,2,3,4-tetrol.Chiral 1-O-benzyl glycerol can alternatively be used to form thecorresponding glycerol epoxide, e.g. according to the proceduredescribed by S. Takano et al. in Synthesis 116 (1983). Inversion can beaccomplished, for example, using the techniques described by Mitsunobuin Bull. Chem. Soc. Jap. 49:510 (1976) or by H. Redlich and W. Franckein Agnew. Chemie. Int'l. Ed. Eng. 19:630 (1980) to form the2S,3S-1,2-anhydro-3,4-arylidene-butane-1,2,3,4-tetrol isomer if desired.

The resultant epoxide is then reacted with a carbon atom source whichundergoes an addition reaction with the epoxide group (e.g. a cyanogroup) to open the epoxide ring and form a corresponding 1-substitutedbutane-2,3,4-triol having five carbon atoms, e.g.4R,3S-4,5-O-benzylidine-3,4,5-trihydroxy pentanonitrile. The onlyrequirement for such a carbon atom source appears to be the ability toform a negatively charged carbon atom. Several such reactants are knownin the art and include but are not limited to the presently preferredcyanide, dithianes and arylmethyl sulfoxides.

Also suitable as carbon atom sources are thiazoles, e.g. as described byA. Dondoni et al. in Agnew. Chem. Int. Ed. Eng. 25:835 (1986); dithianesand dithiolanes (which can be considered as masked formaldehydes) asdescribed by B. T. Grobel et al. in Synthesis 357-402 (1977);oxazolines-, e.g. as described by A. I. Meyers et al. in Agnew. Chem.Int. Ed. Eng. 15:270-281 (1976); methyl methylthiomethyl sulfoxide, asdescribed by K. Ozura et al. in Tetrahedron Lett. 3653 (1974); etc. Suchother suitable groups are generally less preferred because they requirean additional subsequent reaction, e.g. the addition of an oxazole orthiazole group requires subsequent reduction, while the addition of asulfoxide requires a Pummerer rearrangement with acetic anhydride, e.g.,as described by W. E. Parham et al., in J. Org. Chem. 33:4150-4154(1968).

The resultant intermediate compounds, e.g.4R,3S-4,5-O-benzylidine-3,4,5-trihydroxy pentanonitrile, contain twochiral carbon atoms and are accordingly capable of existing in fourpotential isomeric forms. For two of these isomeric forms, it isconvenient to invert the single unprotected hydroxyl group at the3-position using known techniques prior to masking it by knowntechniques such as those described herein.

The added carbon moiety is then reduced, e.g. a cyano group added byreaction With a nitrile can be reduced, preferably using DIBAL(diisobutyl aluminum hydride); these compounds have been found to beparticularly useful in cleaving benzylidine acetals in both cleaving theO-benzylidine hydroxyl protecting groups and in converting them into abenzyl ether, as has been described by S. Takano et al. in Chemo Letters1593-1596 (1983) published by the Chemical Society of Japan. Otherversions of such a reaction have been described by E. Winterfeldt inSynthesis 617-626 (1975). Other carbon fragment moieties can be reducedby techniques likewise known in the art, e.g. see Fieser and Fieser,Reagents for Organic Synthesis, pages 260-262 (1967).

For those cases wherein the added carbon fragment does not requirefurther reduction, a broader choice of benzylidene acetal reducing agentis available, e.g. LiAH₄ /AlCl₃ as described by J. Gelas in Adv.Carbohydr. Chem. Biochem. 59:39 71-155, especially at pages 121-137(1981) or NaCNBH₃ /HCl as described by P. J. Garegg et al. in Carbohydr.Res. 108: 97-101 (1982).

As previously indicated, reduction of the3-O-protected-4,5-di-O-protected derivative, e.g. 4R,3S-4,5-O-benzylidine-3,4,5-trihydroxy pentanonitrile, with DIBALsimultaneously reduces the nitrile group to form a corresponding3,5-di-O-protected-2-deoxy-pentofuranose or a glycoside thereof; theD-sugars are obtained when the intermediates have been prepared startingfrom isoascorbic acid in the reaction scheme and the L-sugars fromascorbic acid as the original starting material, the L-- or D--configuration of the acid being determined by that of the C5 carbon atom(which is the C4 carbon atom in the starting tetrol).

Preferably the base used in this aspect of the present invention is anucleoside base selected from the group consisting of substituted orunsubstituted adenine, guanine, thymine, uracil and hypoxanthine. Thebase can be unsubstituted or substituted by halogen, seleno, thio,amino, alkylamino, arylamino, oxo, alkyl, aryl, alkoxy, aryaloxy,alkoxyaryl or arylalkoxy, e.g. guanine substituted at the 6- or 8-position, especially by a halogen, e.g. chlorine; 6-chloroguanine isespecially preferred. The reaction scheme for this aspect of the presentinvention is shown in FIG. 2, with the intermediates therein shown asFormulae 15-17 and the analogues themselves as Formula 19.

In a fifth aspect, the present invention provides a method for preparingisomerically pure (R)-- or (S)-enantiomers of Formula 18 in FIG. 2,wherein R' and R" have the above-indicated values and R is a group ofthe formula CnHm wherein n is an integer from 1-24, preferably 12-20,and in is equal to 2n+1, 2n-1, 2n-3, 2n-5 or 2n-7 provided that R"O isstable against cleavage under conditions wherein RO or R'O can becleaved.

Preferred values in the above formula are those wherein n in 12-20 and mis 2n+1, 2n-1 or 2n-3, especially where n is 14-18 and particularlywhere the product is in the form of a mixture of enantiomers in which nhas a plurality of the above-indicated values, e.g. wherein n=16 and 18as in palmityl and the product is platelet activating factor.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative and not limitative ofthe remainder of the disclosure in any way whatsoever. In the followingExamples, the temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight.

Melting points were determined on a Thomas-Hoover melting pointapparatus (capillary method) and are uncorrected. IR spectra wereobtained on a Beckman IR-8 spectrophotometer. Optical rotations weremeasured on a Perkin-Elmer Model 141 polarimeter. The 1H NMR spectrawere recorded on a Varian EM-390 MHz spectrometer, and CDCl₃ was used assolvent unless otherwise indicated. Chemical shifts are expressed inparts per million with respect to Me₄ Si. TLC was performed on precoated(0.25 mm) silica gel 60F-254 plates purchased from EM Laboratories,Inc., and separated materials were detected with ultraviolet and/or byspraying with 20% sulfuric acid followed by charring. EM silica gel 60(70-230 mesh ASTM) was employed for routine column chromatography and230-400 mesh ASTM for flash chromatography. The term "usual workup"means washed with water, dried with magnesium sulfate, filtered andevaporated. Evaporations were performed with a Buchi Rotavapor at 40° C.unless otherwise stated. Elemental analyses were performed byM-H-W-Laboratories., Phoenix, Ariz.

EXAMPLE 1

This Example illustrates the preparation of alky-protected chiralglycerchiral glycerol derivatives.

To a suspension of 1,2R-O-isopropylidene erythritol (0.012 mol) indistilled water (15 ml) containing sodium phosphate (0.123 g) was addedsodium metaperiodate (2.72 g, 0.013 mol) keeping the temperature below35° C. The suspension was stirred at room temperature for 15 min. Sodiumiodate began to precipitate and the addition of methanol (15 ml)completed the precipitation. The solid was filtered off, washed withmethanol (5 ml×2) and was discarded. A sodium phosphate buffer (8 ml)was added to the filtrate which was cooled in an ice bath. Sodiumborohydride (0.61 g, 0.016 mol) was added in small portions in about 30min. (foaming occurs), and stirring was continued at room temperaturefor 3 hrs. Excess sodium borohydride was destroyed with acetone (3 ml).Filtration evaporation gave an oil which was partitioned between asaturated solution of sodium chloride and chloroform. Drying of theorganic layer over magnesium sulfate followed by evaporation gave theproduct in 80% yield; [alpha] _(D) =-11.7 (c=1.03, MeOH)

EXAMPLE 2

This Example illustrates the preparation of aryl-protected chiralglycerol derivatives.

Starting with 3,4-S-O-dibenzyl-erythritol, R-1,2-O-Dibenzylglycerol wasobtained in an identical manner to the procedure described above in 64%yield;

[alpha] _(D) =+1.31 (c=3.21, EtOH)

EXAMPLE 3

Preparation of 2R,3S-3,4-epoxy-1,2-O-benzylidene-butane-1,2-diol.

8 grams (0.038 mole) 2R,3S-1,2-O-benzylidene-butane-1,2,3,4-tetrol werereacted with 0.0438 mole triphenyl phosphine in the presence of 0.0438mole diethylazidodicarboxylate (DEAD) in 88 ml benzene with heating.After the addition, the benzene was removed and the residue distilled(0.04 mm) to give a 7.003 gram mixture of the benzylidene epoxide and H₂DEAD in a ratio 21:33. Ethyl ether was added to precipitate the H₂ DEAD,which was collected. A mixture of the benzylidene epoxide and H₂ DEADwas obtained after removing ether from the filtrate.

The undistillable residue was dissolved in chloroform and absorbed on 20grams of silica gel, 230-400 mesh. This was eluted with a 10% ethylacetate (EtAc) in hexane, giving 0.339 gram of the epoxide. Twofractions were combined and chromatographed on silica gel; elution with10% EtAc in hexane gave 3.3831 gm (46.3%) of the pure benzylideneepoxide.

EXAMPLE 4

Preparation of 2S,3S-3,4-epoxy-1,2-O-benzylidene-butane-1,2-diol.

0.1567 mole of 2S,3S-1,2-O-benzylidene-butane-1,2,3,4-tetrol was reactedwith 0.18 mmole triphenyl phosphine and 0.58 mmole DEAD in 362 ml drybenzene. After addition of reactants, benzene was removed and theresidue heated at 145° C. and 0.15 mm to give 2.3 grams of thebenzylidene epoxide. The unfilterable product was dissolved inchloroform and absorbed on 440 grams of silica gel, which was charged ontop of a silica gel column (60-230 mesh, 150 grams) and eluted with 5%EtAc in hexane, giving 8.4269 grams of the benzylidene epoxide. Combinedwith a second elution, the total yield was 10.4169 grams or 35%.

EXAMPLE 5

This example shows addition of a carbon fragment to the epoxide.

0.0113 mole of 2R, 3S-3,4-epoxy-1,2-O-benzylidene-butane1, 2-diol wasreacted with 0.0113 mole KCN and 0.0104 mole MgSO₄. 7H₂ O in 3.6 gramsof water. The crude 2R, 3S-4,5-O-benzylidene-3-hydroxy-pentonitrileproduct was chromatographed over 30 grams of silica gel, gave four spotsupon sequential elution in 10% EtAC in hexane (two samples) and 20% EtACin hexane (the next two samples). 1.7480 grams of the desired productwas obtained, giving a yield of 78.9% based on the starting materialsrecovered.

EXAMPLE 6

This example shows the addition of a benzyl group.

1.094 mmole of 2R,3S-4,5-O-benzylidene-3-hydroxy-pentanonitrile in 1.5ml of dry dimethylformamide (DMF) was reacted with 1.20 mmole NaH and1.117 mmole of benzyl bromide in 0.5 ml of dry DMF. NaH was pre-washedwith benzene and 15 ml of dry DMF added. To this was added the cyanoalcohol in 1.5 ml of dry DMF. After 5 minutes of stirring, a solution ofbenzyl bromide in 0.5 ml DMF was added slowly and stirring continued forthree quarters of an hour. The reaction mixture was poured into 10 ml ofbuffer and extracted with ether (4×20 ml). The extract was washed withwater (6×10 ml) and dried over MgSO₄. Evaporation of ether gave 0.2608grams of crude product, which showed three spots upon chromatography,i.e., benzyl bromide, starting material and the benzylated cyanocompound.

The product was chromatographed over silica gel and eluted with hexanegiving benzyl bromide. Further elution with 10% EtAc in hexane gave1.085 gram (32.1%) of 2R,3S-3-O-benzyl-4-5-O-benzylidene pentanonitrile,the structure of which was confirmed by both NMR and IR.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those specifically used inthe examples. From the foregoing description, one skilled in the art towhich this invention pertains can easily ascertain the essentialcharacteristics thereof and, without departing from the spirit and scopeof the present invention, can make various changes and modifications toadapt it to various usages and conditions.

Industrial Applicability

As can be seen from the present specification and examples, the presentinvention is industrially useful in providing a process and compoundsuseful as intermediates for the preparation of R-- and S-- glycerolderivatives, common building blocks for a number of chiral natural andsynthetic products, from a single intermediate in high yields.

What is claimed is:
 1. A process for preparing an enantiomerically pure2-deoxy pentofuranose selected from the group consisting of2-deoxy-L-xylose, 2-deoxy-L-ribose, 2-deoxy-D-xylose and2-deoxy-D-ribose, which comprises:(a) selecting4,5-O-arylidine-3-O-protected 3,4,5-trihydroxy pentane derivatives ofthe Formulae ##STR1## wherein Ar and R are each an O-protecting groupwherein Ar is an aromatic or a substituted aromatic selected from thegroup consisting of aryl; alkaryl; o-, m- or p-tolyl; o-, m- orp-methoxyphenyl; o-, m- or p-chlorophenyl; or alpha- or beta-naphthyl,the substituents selected from the group consisting of 1-3 lower alkylgroups, 1-3 lower alkoxy groups or 1-3 halogen atoms and R is selectedfrom the group consisting of an aliphatic, cycloaliphatic, alkaryl orsilyl; wherein the aliphatic or cycloaliphatic is preferably of up tosix carbon atoms; b) reducing with an alkali metal borohydride thepentane derivative to form 3,5-di-O-protected-2-deoxy pentanofuranosehaving the same chirality as the pentane, of the Formulae ##STR2##separating by filtration a selected enantiomerically pure 2-deoxypentofuranose; and recovering by chromatographic elution said separated2-deoxy pentofuranose.
 2. The process of claim 1 wherein the aryl isselected from the group consisting of phenyl, naphthyl or substitutedphenyl and the alkaryl is selected from alkylphenyl or substitutedalkylphenyl; the substituents are selected from the group consisting of1-3 lower alkyl groups, 1-3 lower alkoxy groups, or 1-3 halogen atoms.